| Title | Physiologically-Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin. | | Author(s) | Quinney SK, Zhang X, Lucksiri A, Gorski JC, Li L, Hall SD | | Institution | 1 Indiana University School of Medicine; | | Source | Drug Metab Dispos 2009 Nov 2. | | Abstract | The prediction of clinical drug-drug interactions (DDI's) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3A, as in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g. midazolam, fail to account for nonlinear metabolism of clarithromycin. A semi-physiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and nonCYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K(I) and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 muM for K(i) and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6 fold-change in i.v. midazolam AUC following 500 mg clarithromycin p.o. twice daily was consistent with clinical observations. While the mean predicted 5.3 fold-change in the AUC of p.o. midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K(I), k(inact), and CYP3A half-life than hepatic CYP3A. This semi-PBPK model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Further, this model framework can be applied to other mechanism-based inhibitors. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19884323 |
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